tbuckley/cabot-search huggingface dataset:
CTIM-20. SYSTEMIC IMMUNE CORRELATES ASSOCIATED WITH LONG-TERM SURVIVAL AFTER THERAPEUTIC ADENOVIRUS (DNX2401) PLUS INTERFERON GAMMA FOR RECURRENT GLIOBLASTOMA EFFECT TRIAL (TARGET): A RANDOMIZED PHASE 1 TRIAL
Authors: Chibawanye Ene, Sanjay Singh, Lynette Phillips, Raja Venkataraman, Vinay Puduvalli, Deep Singh, Nam Tram, James Long, Martin Brady, Raghu Raghavan, Frank Tufaro, Brett Ewald, P J Anand, J Bradley Elder, Karen Fink, W K Alfred Yung, Marta Penas-Prado, Nick Navin, Benjamin Larman, Candelaria Gomez-Manzano, Juan Fueyo-Margareto, Joanna Peterkin, Frederick Lang
Journal: Neuro-Oncology (2023)

Abstract Anti-tumor immune response following oncolytic virus treatment of glioblastoma may be enhanced by immune activating therapies. Here, in this Phase Ib, multicenter, randomized, open-label study we evaluated the combination of intra-tumoral delivery of oncolytic virus DNX-2401 with subcutaneous interferon gamma (IFN-γ) a T-helper 1 response activator in 37 patients with recurrent glioblastoma. In part 1, 27 patients were randomized 2:1 into DNX-2401 with IFN-γ and DNX-2401 alone with intra-tumoral DNX-2401 administered via a standard biopsy needle. In part 2, 10 patients received intra-tumoral DNX-2401 via an FDA-approved Alcyone MEMS Cannula designed to prevent backflow at high infusion flowrates. DNX-2401 was well tolerated but the addition of IFN- γ was not well tolerated. The primary efficacy endpoint, objective clinical response, was not met. The secondary endpoint of 12-month overall survival for DNX-2401 with IFN-γ, DNX-2401 alone and DNX-2401 via Cannula were 33%, 22%, 0% respectively. The 18-month OS for DNX-2401 with IFN-γ, DNX-2401 alone and DNX-2401 via Cannula were 25%, 9%, 0% respectively. The DNX-2401 with IFN- γ cohort had the most long-term survivors (44.2, 23.7, 20.6 and 20.1 months). Systemic antibody and immune cell profiling following DNX-2401 treatment showed that long term survivors had significantly higher anti-adenovirus specific antibody reactivity and a higher activated CD8+ effector memory T-cell sub-population at 2 months post-treatment relative to baseline. This systemic immune response did not occur in short term survivors following DNX-2401 treatment. Overall, these data suggest that an early and robust systemic adaptive immune response could be used as a biomarker for long term survival following DNX-2401 treatment of recurrent glioblastoma independent of other salvage treatments administered following disease progression during the trial. (Clinical Trial.gov registration: NCT02197169).
PATH-47. MOLECULAR MARKERS ASSOCIATED WITH SURVIVAL IN GRADE 3 MENINGIOMA
Authors: Kira Tosefsky, Alexander Rebchuk, Justin Wang, Karina Chornenka, Gelareh Zadeh, Serge Makarenko, Stephen Yip
Journal: Neuro-Oncology (2023)

Abstract Meningiomas have historically been graded using histologic features. However, a subset of meningiomas progress in manners inconsistent with their histologic grading. While TERT promoter (TERTp) mutations and CDKN2A/B homozygous deletion were recently added to the WHO 2021 classification criterion for grade 3 meningioma, the precise prognostic implications of these and other molecular features remain to be fully characterized. In this case series, we explored whether molecular markers were associated with clinical outcomes in a single-center cohort of grade 3 intracranial meningiomas. Demographic, clinical and histopathological information were obtained from the electronic medical records of all grade 3 meningioma cases surgically treated at a tertiary center between 2007-2020. Tissue blocks were reviewed by a neuropathologist and tested for TERTp mutations, BAP1 and CDKN2A/B copy number profiles, and BAP1, p16 and MTAP expression by immunohistochemistry (IHC). Predictors of survival were identified by Cox regression. Fifteen patients (8 female, 7 male) with a median age of 64 (IQR: 48, 74) years were included. Eight (53%) tumors were classified as anaplastic, 6 (40%) as rhabdoid and 1 (6.7%) as papillary. One (7%) rhabdoid tumor exhibited BAP1 loss, while four (27%) tumors harbored TERTp mutations and 3 (20%) demonstrated homozygous CDKN2A/B loss. All three tumors exhibiting homozygous CDKN2A/B loss were MTAP-negative, while two were p16-negative and the third showed focal (&amp;lt; 50%) p16 loss by IHC. TERTp mutations and CDKN2A/B copy number status were associated with significant reductions in RFS (HR = 6.90, 95% CIs: 1.13-42.2 and HR = 12.0, 05% CIs: 1.51-95.4, respectively) and OS (HR = 8.72, 95% CIs: 1.87-40.6 and HR = 6.18, 95% CIs: 1.30-29.4, respectively). The associations between reduced OS and TERTp mutations and CDKN2A/B status remained significant after adjusting for Simpson resection grade. Our findings support using TERT p mutations and CDKN2A/B status for prognostication in grade 3 meningioma.
NCMP-23. EVALUATION OF IMMUNOTHERAPY EFFECTS IN CANCER PATIENTS ON EPILEPTIFORM ACTIVITY
Authors: Kaela Wong, Ayush Thakur, Elizabeth Zuidema, Edward Avila, Xi Chen, George Lai, David Mao
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND/OBJECTIVE Immune checkpoint inhibitors are associated with increased risk of autoimmune neurologic conditions, both in the peripheral and central nervous system. Increased activation of the immune system can lower seizure threshold, potentially increasing a patient’s risk of seizures. We hypothesize that patients treated with immune checkpoint inhibitors have a higher rate of seizures. METHODS We retrospectively reviewed 465 cancer patients undergoing electroencephalography (EEG) monitoring performed at Memorial Sloan Kettering Cancer Center from January 2022 to March 2023. Data was gathered from an EEG RedCap database containing patient demographic and seizure data. Patients were separated based on whether they had received immune checkpoint inhibitors (+ICI) prior to seizure occurrence or were never exposed to immune checkpoint inhibitors (-ICI) and had a seizure. Patient cancer type and presence of brain lesions (primary or metastases) were also reviewed. RESULTS Out of 465 patients, 109 received immune checkpoint inhibitors (+ICI) during their treatment. Seven of those patients were reported to have had at least one seizure (7/109, 6.42%) following treatment with ICI. The remaining 356 patients did not undergo immune checkpoint inhibitor treatment (-ICI), of which 30 were reported to have had at least one seizure (30/356, 8.43%). Of the +ICI patients who were experiencing seizures, 5 of them had brain lesions; 4 had primary brain tumors and 1 had brain metastases. Of –ICI patients, 21 patients had brain lesions; 15 had primary brain tumors and 6 had brain metastases. DISCUSSION Although immune checkpoint therapy may lead to increased activation of the immune system, our data did not reveal a higher incidence of seizures. Limitations to our study include its retrospective design, low number of patients, and low overall number of seizures captured on EEG.
MODL-05. ELUCIDATING THE EPIGENETIC DRIVEN TRANSCRIPTIONAL PROGRAM UNDERLYING THE INVASIVE PHENOTYPE OF THE NOVEL EGFRA289VARIANT OF GBM
Authors: Benjamin Lin, Julia Ziebro, Abigail Shelton, Kasey Skinner, Ryan Bash, Satoru Osuka, Sunil Sudarshan, Zev Binder, Donald M O'Rourke, David Nathanson, Frank Furnari, Christopher Miller
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma (GBM) is a devastating malignant brain tumor with a dismal 15-month median survival. Current treatments have not been successful at preventing recurrence, thus novel therapeutic modalities are urgently needed. EGFR is a tyrosine kinase receptor that is commonly mutated in ~60% of GBM and is an attractive target for GBM precision oncology. Aberrant EGFR signaling drives tumor proliferation and maintenance, thus further study of common EGFR alterations in GBM, including interstitial deletions (EGFRvIII) and missense mutations (EGFRA289), is needed to develop effective EGFR-targeted therapies. This is especially important in the context of a retrospective study that showed EGFRA289 driven GBM was more clinically aggressive. EGFRA289 positive GBM had a unique, invasive radiographic signature on magnetic resonance imaging (MRI) and patients had a significantly shorter median overall survival of 6-months. We hypothesize that the malignant clinical phenotypes of EGFRA289 GBM are driven by unique epigenomic and transcriptomic, collectively referred to as (epi)genomic, programs linked to EGFRA289 signaling. Prior studies using established cell lines show that EGFRvIII overexpression drives malignant (epi)genomic programs mediated by transcription factor (TF) activation. To better understand variant specific EGFR biology in GBM, we have developed novel genetically engineered mouse astrocyte (mAc) models that overexpress wtEGFR (MA-WT), vIII (MA-v3), and EGFRA289V (MA-A289V). Phospho-immunoblots show that these mAc models have differential EGFR ligand dependance, which match published studies. Despite this difference in EGFR signaling, all mAc models have similar sensitivities to EGFR tyrosine kinase inhibitor (TKI) treatment. However, MA-A289V is more proliferative and migratory compared to the other mAc variants. Preliminary RNA-Seq on our mAc models has identified similar and unique TFs differentially expressed (DE) between MA-v3 and MA-A289V when compared to parental MA-C. Integration of RNA-Seq and CUT&amp;RUN followed by mechanistic genetic interrogation will elucidate the relationship between EGFR variant-specific (epi)genomic mechanisms and their unique malignant phenotype.
INNV-29. THE CLEARPOINT PRISM® LASER ABLATION SYSTEM: A NEW PLATFORM FOR LASER INTERSTITIAL THERMAL THERAPY (LITT) IN NEURO-ONCOLOGY
Authors: Hannah Wilson, Clark Chen
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Laser interstitial thermal therapy (LITT) has advanced the surgical treatment of brain cancer. However, technical constraints in the first-generation laser ablation systems limit the full potential of this technology. ClearPoint Prism® Laser Ablation System was developed to overcome many of these limitations, including a larger ablation window, a faster refresh rate for magnetic resonance thermometry, and integration with an MRI-compatible stereotactic system. This system was FDA cleared for neurosurgical use in 2022. METHODS We prospectively followed the first three patients who underwent LITT using the ClearPoint Prism® Laser Ablation System in the U.S. to establish feasibility and safety of this technology platform. RESULTS Three patients underwent procedures involving MRI-guided needle biopsy followed by LITT. The radial error of stereotaxis relative to the intended target ranged 0.8-1.6 mm (with a median of 1.0 mm). Definitive diagnosis was achieved in all cases. The average time required to establish the trajectories was 98.7 + 16.6 minutes. The average time required to perform the biopsy and LITT was 110 + 19.3 minutes. These times are not statistically different from our published results for comparable procedures using other available LITT systems. The average LITT time required to achieve ablation of &amp;gt; 1cm radius was 49 seconds (range: 29-133 seconds). There were no procedural complications. All patients were discharged home by postoperative day three. The postoperative MRIs demonstrated expected ablation findings consistent with intraoperative thermometric assessment. With a median follow-up of 219 days (range: 185-259 days), there were no 30-day readmission, 90-day emergency visits, or wound complications. CONCLUSION In this study, we provide the clinical outcome of the first three patients in the U.S. who underwent LITT through the FDA cleared ClearPoint Prism® Laser Ablation System. The system has distinct advantages that warrant consideration in further investigations and clinical applications.
CTIM-34. JACOB: JOINT ADMINISTRATION OF CDNA FOR <i>TP53</i>, CHECKPOINT INHIBITION, AND BOOST/HYPO FRACTIONATED RADIATION. A PHASE 0/1 STUDY IN CHILDREN WITH RECURRENT, PROGRESSIVE, OR REFRACTORY CNS MALIGNANCIES
Authors: Adriana Fonseca, Sang Soo Kim, Russell Cruz, Matthew Ladra, Kathleen Pirollo, Esther Chang, Roger Packer, Eugene Hwang
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Pediatric patients with recurrent, progressive, or refractory brain tumors have dismal prognoses and few therapeutic options. Due to the complex biological mechanisms of resistance in these tumors, targeted agents and immunotherapeutic approaches in isolation have yielded disappointing results. The combination of SGT-53, anti-PD-1, and hypofractionated radiation has shown encouraging results in preclinical studies. SGT-53 is a novel nanoparticle carrying cDNA encoding human wild-type human TP53; the nanoparticle uses a single-chain antibody fragment recognizing the human transferrin receptor, leading to excellent blood-brain barrier penetrance and anti-tumor targeting. TP53 therapy work synergistically with immune checkpoint inhibitors like anti-PD-1. Hypofractionated radiation provides additional synergy, increasing vascular access, cytokine production and activating tumor-specific T-cells. METHODS JACOB is a prospective, phase 0/1 clinical trial to evaluate the safety and efficacy of SGT-53 in combination with hypofractionated radiation and anti-PD-1 in children with recurrent, progressive, or refractory CNS malignancies. Inclusion criteria: patients age ≥ 3 and ≤ 21 years, measurable disease, performance status &amp;gt;50 and adequate organ function. The 3 + 3 de-escalation design will be used to determine the maximum tolerated dose (MTD) of SGT-53 in combination with ICI and radiation. Dose limiting toxicities will be evaluated. SGT-53 will be administered two times per week. Hypofractionated radiation will be given in week 2, and anti-PD-1 (once in 2 weeks) will begin on the second week of treatment. A maintenance phase of SGT-53 and anti-PD-1 will be continued for up to 12 months. Primary endpoints evaluate toxicities related to SGT-53 and plasma pharmacokinetics. Secondary and exploratory endpoints include best radiological response, and immunobiological markers. Twelve patients will be treated in the phase I/dose de-escalation cohort. After the MTD has been identified, a target validation/ phase 0 cohort will include up to 4 patients receiving 2 doses of SGT-53 prior to undergoing surgical resection to determine tissue-specific response.
MODL-08. A COMPENDIUM OF SYNGENEIC, TRANSPLANTABLE PEDIATRIC HIGH-GRADE GLIOMA MODELS REVEALS SUBTYPE-SPECIFIC THERAPEUTIC VULNERABILITIES
Authors: Michael McNicholas, Antonella De Cola, Zahedeh Bashardanesh, Amelia Foss, Cameron Lloyd, Steven Hebert, Damien Faury, Augusto Faria Andrade, Nada Jabado, Claudia Kleinman, Manav Pathania
Journal: Neuro-Oncology (2023)

Abstract Pediatric high-grade gliomas (pHGGs) are lethal, incurable brain tumors frequently driven by clonal mutations in histone genes. They often harbor a range of additional genetic alterations that correlate with different ages, anatomical locations, and tumor subtypes. We developed models representing 16 pHGG subtypes driven by different combinations of alterations targeted to specific brain regions. Tumors developed with varying latencies and cell lines derived from these models engrafted in syngeneic, immunocompetent mice with high penetrance. Targeted drug screening revealed unexpected selective vulnerabilities— H3.3G34R/PDGFRAC235Y to FGFR inhibition, H3.3K27M/PDGFRAWT to PDGFRA inhibition, and H3.3K27M/PDGFRAWT and H3.3K27M/PPM1DDC/PIK3CAE545K to combined inhibition of MEK and PIK3CA. Moreover, H3.3K27M tumors with PIK3CA, NF1 and FGFR1 mutations were more invasive and harbored distinct additional phenotypes, such as exophytic spread, cranial nerve invasion and spinal dissemination. Collectively, these models reveal that different partner alterations produce distinct effects on pHGG cellular composition, latency, invasiveness, and treatment sensitivity.
RADT-21. LINEAR ACCELERATOR BASED RADIOSURGERY WITH DYNAMIC CONFORMAL ARCS FOR PATIENTS WITH MULTIPLE BRAIN METASTASES: A PROSPECTIVE COHORT STUDY
Authors: Shih-Ting Huang, Yen-Ting Liu, Kuan-An Chu, Tsu-Hsien Huang, Sin-Yin Chen
Journal: Neuro-Oncology (2023)

Abstract PURPOSE Linear accelerator (LINAC)-based stereotactic radiosurgery (SRS) is gaining popularity as an alternative due to its high delivery efficiency and improved accessibility. This study focuses on the radiosurgery protocol of a single institution, utilizing single-isocenter multi-target SRS treatment with an inverse-optimized dynamic conformal arc technique. Materials &amp; METHODS A prospective cohort study was conducted from August 2020. The study protocol was approved by the Research Ethics Committee. Patients with brain tumors referred for SRS were treated based on the indications. Prescription doses were determined by target size and radiation oncologists. The protocol included a 1-2 mm expansion of tumors for the planning target volume (PTV), with a requirement of at least 85% PTV coverage. At least three non-coplanar arcs are needed. Competing risk survival analysis was used to assess the cumulative incidence of failure. RESULTS A total of 57 patients with 190 brain tumors underwent SRS in this study. 12 patients (21.1%) received at least 2 radiation courses for recurrent lesions. Tumor sizes ranged from 0.45 to 8.0 cm (median 1.41 cm). The maximal dose relation ranged between 71.5% and 91.4% (median 81.6). The conformal index ranged from 1.08 to 2.19 (median 1.19), and the dose gradient index ranged from 2.19 to 6.95 (median 3.59). The 1-year cumulative incidence of local failure and intracranial distant failure rates were 10.8% and 35.6%, respectively. CONCLUSION LINAC-based SRS using dynamic conformal arcs achieves optimal tumor coverage and a high dose gradient with ease. It demonstrates a low rate of local failure, effectively protects normal brain tissue, and allows for the postponement of whole brain radiotherapy, enabling patients to maintain a normal quality of life. In conclusion, LINAC-based SRS with dynamic conformal arcs may be a beneficial treatment option for brain metastases, even with a high lesion count, particularly in institutions equipped with LINAC.
SURG-20. USEFULNESS OF PHOTODYNAMIC THERAPY (PDT) WITH TALAPORFIN SODIUM FOR GLIOBLASTOMA
Authors: Takashi Sasayama, Kazuhiro Tanaka, Hiroaki Nagashima, Yuichi Fujita, Shunsuke Yamanishi
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Photodynamic therapy (PDT) with talaporfin sodium uses the toxicity of singlet oxygen generated by a reaction between a photosensitizer in tumor cells and light with a specific wavelength. PDT was introduced in our hospital in April 2017. We retrospectively analyzed the glioblastoma (GBM) patients treated with PDT and compared with the patients who did not receive PDT. MATERIAL AND METHODS From April 2015 to March 2023, total 145 patients with GBM were treated in our hospital. Among them, patients of recurrence, IDH mutant, biopsy and no chemo/radiotherapy were excluded. The patients’ characteristics, adverse event, changes of the MR image, recurrence pattern, outcome of the patients were analyzed. In addition, survival time of the patients between the PDT group and the non-PDT group was compared. RESULTS A total of 80 GBM patients were analyzed. Forty-four patients received PDT. 4 patients had adverse event; cyst formation, venous infarction, brain swelling, and delirium. In most of the patients, linear high signals of 5-7 mm on DWI were detected at the surface of the resected cavity and matched the PDT-irradiated area from 1 day after PDT. All hyperintense signal on DWI disappeared in about 30 days without any neurological deterioration. Sixty-seven patients had recurrence (PDT group; 33 cases, non-PDT group; 34 cases). Recurrence pattern of distant/dissemination were significantly increased in the PDT group compared with the non-PDT group. The PDT group tended to have longer survival in both OS (p = 0.08) and PFS(p = 0.07) than the non-PDT group. In multivariate analysis for OS, age and MGMT promotor methylation were significant prognostic factors, but not PDT. CONCLUSION PDT was safety and useful for GBM. However, the PDT group had significantly more distant/disseminated recurrences than the non-PDT group. We need to analyze more cases to clarify efficacy and recurrence patterns.
SURG-36. CLINICO-RADIOLOGICAL PARAMETERS, MOLECULAR AND CHROMOSOMAL ALTERATIONS AFFECTING SURGICAL OUTCOME OF PETROCLIVAL MENINGIOMAS
Authors: Ashish Suri, Vaishali Suri
Journal: Neuro-Oncology (2023)

Abstract Petroclival meningiomas were reviewed for correlation of extent of resection with clinico-radiological parameters and molecular/chromosomal alterations. 53 surgical procedures in 50 patients of petroclival meningioma were performed. Cavernous sinus and sellar extension were present in 37(69.8%) and 5(9.4%) respectively; contralateral extension in 10(20%). Modified anterior transpetrous rhomboid-MATRA (44=83.0%) was the most commonly used approach, followed by retrosigmoid (2=3.8%), and combined (7=13.2%) approaches. Hypointense tumors on T2-weighted MRI (OR:5.85;95%CI:1.70-20.41) and presence of brainstem edema (OR:4.53;95%CI:1.36-15.12) were found to be significant factors increasing the likelihood of subtotal resection-STR (p = 0.004 &amp; p = 0.011 respectively). In the presence of both tumor T2-hypointensity and brainstem edema, there was significant increase in the likelihood of STR (p = 0.001;OR:25;95%CI:3.52-177.48). The most common cranial nerve to suffer new-onset deficit postoperatively was found to be VI nerve(19=35.8%) followed by V(9=16.9%) and VII(8=15.8%) nerves. On long-term follow-up, 38 patients had good outcome. Out of the 16 cases for which molecular analysis was performed, no specimen was found to have pTERT-C228T,C250T, AKT-1, E17K and SMO-L412F,W535L mutations. Eight (50.0%) cases showed H3K27me3 loss while 5 (31.25%) had hemizygous CDKN2A deletion. All(100%) patients harboring H3K27me3 loss and/or hemizygous CDKN2A deletion had cavernous sinus extension compared to 62.5% patients without H3K27me3 loss and 72.7% with hemizygous CDKN2A retention. Similarly, hemizygous CDKN2A deletion and H3K27me3 loss are associated with increase in the rate of brainstem edema from 27.3% to 60% and 25% to 50% respectively. Cases (n = 4) with both these alterations have 100% cavernous sinus extension and 75% chances of brainstem edema and lack of arachnoid plane. The MATRA is a versatile approach for petroclival meningiomas with good surgical outcome and acceptable complication rates. T2 hypointense tumor and brainstem edema on pre-operative imaging are significant predictors of STR. H3K27me3 loss and hemizygous CDKN2A deletion may be associated with cavernous sinus extension suggesting their role in tumor spread.